Systemic lupus erythematosus (SLE) is the prototype systemic autoimmune disease, which has the potential to cause substantial morbidity and early mortality. Current treatments for SLE are inadequate, largely due to our lack of understanding about disease etiology. Although genetic factors are clearly implicated in SLE, the genetic complexity of this illness has hampered progress in defining the genetic determinants. However, recent advances in molecular genetic and statistical methodology have provided new tools with which to unravel the genetics of complex diseases such as SLE. We have the following specific aims for this project: 1) We will identify and recruit a total of 1,350 individuals with SLE who have at least 1 living parent or sibling. Each SLE subject will be carefully evaluated to ensure that she/he meets strict criteria for a diagnosis of SLE. Relevant clinical data and DNA will be collected from all SLE subjects, and from their parents and siblings. 2) We will determine whether 10 specific candidate genes are associated with SLE susceptibility. Our primary analytic method will be the transmission disequilibrium test, utilizing parents or siblings of SLE cases as controls. Our choice of genes relates to their known involvement in pathophysiologic processes relevant to SLE and/or supporting evidence from previous genetic studies. Specifically, we will study 3 HLA region genes (HLADQAl, C4A and TNFalpha), 4 genes encoding key T cell receptor or ligand molecules (TCRA and B, CD28/CTLA4 and CD80/CD86), 2 genes encoding cytokine molecules (IL-1ra and IL-10), and FcgammaRIIA, a gene that encodes a molecule with a central role in immune complex processing. The expertise of our study team in the areas of rheumatology, molecular genetics, and statistics, in conjunction with our progress during the past year, ensures a very high likelihood of success for this project. Finally, the families recruited for this study will serve as a valuable resource for future genetic epidemiology studies of SLE. Therefore, the efforts of this project represent an important investment for the future.